Method for producing asymmetric tetrasubstituted carbon atom-containing compound

ABSTRACT

The invention provides an industrial method for producing a spiroaminopyrrolidone derivative, which is an intermediate for producing a quinolone antibacterial agent. 
     The invention provides a method for producing a compound represented by formula (2): 
                         
(wherein n is an integer of 2 to 5; R 1  represents a (substituted) alkyl group or a (substituted) aryl group; and R 2  represents a (substituted) alkoxycarbonyl group, a (substituted) aralkyloxycarbonyl group, a (substituted) aliphatic acyl group, or a (substituted) aromatic acyl group), which includes treating a compound represented by formula (1):
 
                         
(wherein n, R 1 , and R 2  are the same as defined above; and R 3  represents a hydrogen atom, a (substituted) alkyl group, or a (substituted) aralkyl group) under a hydrogen gas atmosphere in the presence of a metallic catalyst.

TECHNICAL FIELD

The present invention relates to a method for producing a quinolonederivative which is expected to serve as an excellent antibacterialagent, to an intermediate compound that is useful in the productionmethod, and to a method for producing the intermediate.

BACKGROUND ART

In respiratory infectious diseases, multi-drug-resistant Pneumococcus isthe most serious therapeutic target. Telithromycin, which is consideredas the most effective drug against the Pneumococcus, induces a graveside effect; i.e., consciousness disorders. Therefore, development of anantibacterial agent which exhibits high antibacterial effect and inducesreduced side effect is envisaged.

Under such circumstances, the present applicant previously found thatquinolone compounds represented by formula (I):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent, or an aryl group which may have asubstituent; and R⁶ represents a hydrogen atom or a fluorine atom) cansolve problems in the therapy of respiratory infectious diseases; forexample, these compounds exhibit excellent bactericidal effect onmulti-drug-resistant Pneumococcus as well as high safety and excellentin vivo behavior, and filed a patent application therefor (PatentDocument 1). These compounds can be produced through condensationreaction between a spiroaminopyrrolidine compound having an asymmetrictetrasubstituted carbon atom represented by (6-1):

or such a spiroaminopyrrolidine compound in which the amino groupattached to the ring is protected by a protective group and aboron-chelate of a quinolone-skeleton compound represented by, forexample, the following formula:

or a carboxylic form of the quinolone-skeleton compound instead of theboron-chelated compound.

Among compounds represented by formula (6-1), a compound in which, forexample, R¹ is a methyl and n is 2 can be synthesized through thefollowing steps: cyclization reaction between t-butyl acetoacetate(starting material) and alkylene dihalide; converting the formed cycliccompound to an amino-cyano compound by use of a cyanide compound (i.e.,Strecker reaction); reducing the cyano group of the amino-cyano compoundto convert to an aminomethyl group, thereby forming a diamino compound;performing ring-closure reaction through intramolecular lactamizationbetween the amino group derived from the cyano group of the compound anda carboxylic moiety of the compound, to thereby form aspiroaminopyrrolidone compound having an asymmetric tetrasubstitutedcarbon atom; subsequently, protecting the amino group and the NH groupof the pyrrolidone moiety of the compound; performing optical resolutionof the racemic mixture through HPLC by use of an optically activecolumn, to thereby form an optically active form; reducing pyrrolidone;and finally, removing the protective group attached to the ring nitrogenatom. The thus-proposed method isolates a single-isomer intermediatecompound which can be employed in introduction of a substituent to the7-position of a quinolone ring and which is used for producing asingle-isomer compound represented by formula (I).

Meanwhile, there has been known a method for producing aspiro-ring-structure pyrrolidine compound having no alkyl group at the3-position of its pyrrolidine ring (Patent Document 2).

Patent Document 1: JP 2005-146386

Patent Document 2: JP 09-208561

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

A study on industrial-scale application of the proposed productionmethod has revealed that, in a step of the aforementioned steps in whichthe cyano group of the amino-cyano compound is reduced to produce anintermediate to be ring-closed to form a spiroaminopyrrolidone,retro-reaction of the amino-cyano compound proceeds, to causeelimination of the cyano group, whereby a starting material of Streckerreaction is produced to thereby lower the yield of the target compound,and, as well, highly poisonous cyanide is possibly released. It has alsobeen revealed that, since the diamino compound formed through reductionin the step serves as a poison to a metallic reduction catalyst, such acatalyst must be used in a large amount. Thus, the aforementionedproduction method has been found to have problems in terms of yield,operability, and environment, for application of the method on anindustrial scale. In addition, in the aforementioned production method,there has been proposed a subsequent step for recovering an opticallyactive form through HPCL employing an optically active column. However,this recovery step is cumbersome in an industrial production method and,therefore, requires considerable improvement.

Thus, an object of the present invention is to find a method forobtaining high-purity optically active compound which method avoidsproblems including release of cyanide generated during carrying out ofthe aforementioned method on an industrial scale, use of a large amountof catalyst, and performing recovery through HPLC employing an opticallyactive column and which realizes suppression of release of cyanide,reduction in amount of catalyst, and formation of a salt with anoptically active acid.

Means for Solving the Problems

The extensive study by the present inventors has revealed that theretro-reaction can be prevented by protecting the amino group ofamino-cyano compound produced through Strecker reaction with anelectron-attractive group, whereby release of cyanide during reductioncan be prevented (i.e., formation of a poisonous substance can beprevented), and the production yield can be elevated. In addition, sincethe amino group is protected, catalyst inhibiting effect is suppressed(i.e., problematic catalyst poisoning can be prevented).

The present inventors have conducted a further study in an attempt todevelop a more efficient production method, and have found that, when anethyl ester is used as a starting material instead of a t-butyl ester,reaction steps from reduction of the cyano group to cyclization throughintramolecular lactamization proceed all at once.

The inventors have also found that a compound in which the cyclic amidemoiety has been reduced can be optically resolved through formation of asalt with an optically active acid. Thus, a method for synthesizing anoptically active spiroaminopyrrolidine compound having asymmetrictetrasubstituted carbon has been accomplished.

The inventors have also developed an effective method of condensing theoptically active compound and a quinolone derivative, thereby realizingan industrially advantageous method for producing a syntheticantibacterial agent. In other words, the inventors have found that thetarget compound can be produced efficiently without introducing aprotective group to the spiroaminopyrrolidine derivative. Thus, theinventors achieved reduction of the number of reaction steps as well asimprovement of production yield.

Accordingly, the present invention provides the following.

[1] A method for producing a compound represented by formula (2):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R² represents an alkoxycarbonyl group which may have asubstituent, an aralkyloxycarbonyl group which may have a substituent,an aliphatic acyl group which may have a substituent, or an aromaticacyl group which may have a substituent), which comprises treating acompound represented by formula (1):

(wherein n, R¹, and R² are the same as defined above; and R³ representsa C1 to C4 alkyl group which may have a substituent, an aralkyl groupwhich may have a substituent, or a hydrogen atom) under a hydrogen gasatmosphere in the presence of a metallic catalyst.[2] A compound represented by formula (1):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R² represents an alkoxycarbonyl group which may have asubstituent, an aralkyloxycarbonyl group which may have a substituent,an aliphatic acyl group which may have a substituent, or an aromaticacyl group which may have a substituent; and R³ represents a C1 to C4alkyl group which may have a substituent, an aralkyl group which mayhave a substituent, or a hydrogen atom).[3] A compound represented by formula (2):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R² represents an alkoxycarbonyl group which may have asubstituent, an aralkyloxycarbonyl group which may have a substituent,an aliphatic acyl group which may have a substituent, or an aromaticacyl group which may have a substituent).[4] A compound represented by formula (3):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R² represents an alkoxycarbonyl group which may have asubstituent, an aralkyloxycarbonyl group which may have a substituent,an aliphatic acyl group which may have a substituent, or an aromaticacyl group which may have a substituent; and R⁴ represents a benzylgroup, a benzhydryl group, or a trityl group, wherein phenyl groupthereof may have, as a substituent, one or more groups selected from thegroup consisting of a nitro group, an alkoxy group, and a halogen atom).[5] A compound represented by formula (4):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom).[6] A method for producing a salt formed from an optically activecarboxylic acid and a compound represented by formula (5-1):

or formula (5-2):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom) or a hydrate thereof, whichcomprises treating a compound represented by formula (5):

(wherein n, R¹, and R⁴ are the same as defined above) with an opticallyactive carboxylic acid in an organic solvent.[7] A salt formed from an optically active carboxylic acid and acompound represented by formula (5-1):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom) or a hydrate thereof.[8] A salt formed from an optically active carboxylic acid and acompound represented by (5-2):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom) or a hydrate thereof.[9] A compound represented by the following formula:

or a hydrate thereof.[10] A compound represented by the following formula:

or a hydrate thereof.[11] A method for producing a compound represented by formula (5-1):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom), which comprises treating a saltformed from an optically active carboxylic acid and a compoundrepresented by formula (5-1):

(wherein n, R¹, and R⁴ are the same as defined above) with a base.[12] A method for producing a compound represented by formula (5-2):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom), characterized in that the methodcomprises treating a salt formed from an optically active carboxylicacid and a compound represented by formula (5-2):

(wherein n, R¹, and R⁴ have the same meanings as defined above) with abase.[13] A compound represented by formula (5-1):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom), a salt of the compound, or ahydrate of any of these.[14] A compound represented by formula (5-2):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom), a salt of the compound, or ahydrate of any of these.[15] A compound represented by the following formula.

[16] A compound represented by the following formula.

[17] A method for producing a compound represented by formula (6):

(wherein n is an integer of 2 to 5; and R¹ represents a C1 to C4 alkylgroup which may have a substituent or an aryl group which may have asubstituent) or an optically active form thereof, which comprisestreating a compound represented by formula (51):

(wherein n and R¹ are the same as defined above; R⁴¹ represents a benzylgroup or a benzhydryl group, wherein phenyl group thereof may have, as asubstituent, one or more groups selected from the group consisting of anitro group, an alkoxy group, and a halogen atom) or an optically activeform thereof in an acidic solvent in the presence of a metalliccatalyst, and under a hydrogen gas atmosphere or in the presence offormic acid.[18] A compound represented by formula (7):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom; and R⁵ represents at-butyloxycarbonyl group, a benzyloxycarbonyl group, a benzoyl group, oran acetyl group), an optically active form of the compound, a salt ofany of these, or a hydrate of any of these.[19] A compound represented by formula (6):

(wherein n is an integer of 2 to 5; and R¹ represents a C1 to C4 alkylgroup which may have a substituent or an aryl group which may have asubstituent), an optically active form of the compound, a salt of any ofthese, or a hydrate of any of these.[20] A compound represented by the following formula, an opticallyactive form of the compound, or a hydrate of any of these.

[21] A compound represented by formula (8):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁵ represents a t-butyloxycarbonyl group, abenzyloxycarbonyl group, a benzoyl group, or an acetyl group), anoptically active form of the compound, a salt of these, or a hydrate ofany of these.[22] A method for producing a compound represented by formula (9-1):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R⁶ represents a hydrogen atom or a fluorine atom; and R⁷represents an amino group which may have a substituent, a C1 to C4alkoxy group which may have a substituent, a hydrogen atom, or ahydroxyl group), which comprises reacting a compound represented byformula (6-1):

(wherein n and R¹ are the same as defined above) or a salt thereof witha boron-chelate of a quinolon-skeleton compound represented by thefollowing formula:

(wherein R⁶ and R⁷ are the same as defined above; and X represents aleaving group) in the presence of a base.[23] A method for producing a compound represented by formula (9-2):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R⁶ represents a hydrogen atom or a fluorine atom; and R⁷represents an amino group which may have a substituent, a C1 to C4alkoxy group which may have a substituent, a hydrogen atom, or ahydroxyl group), which comprises reacting a compound represented byformula (6-2):

(wherein n and R¹ are the same as defined above) or a salt thereof witha boron-chelate of a quinolon-skeleton compound represented by thefollowing formula:

(wherein R⁶ and R⁷ are the same as defined above; and X represents aleaving group) in the presence of a base.[24] A compound represented by formula (9-1):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R⁶ represents a hydrogen atom or a fluorine atom; and R⁷represents an amino group which may have a substituent, a C1 to C4alkoxy group, a hydrogen atom, or a hydroxyl group), a salt of thecompound, or a hydrate of any of these.[25] A compound represented by formula (9-2):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R⁶ represents a hydrogen atom or a fluorine atom; and R⁷represents an amino group which may have a substituent, a C1 to C4alkoxy group, a hydrogen atom, or a hydroxyl group), a salt of thecompound, or a hydrate of any of these.

Effects of the Invention

According to the present invention, the followings are achieved:improvement of product yield by protecting the amino group of anintermediate with an electron-withdrawing group; suppression ofproduction of a poisonous substance; considerable reduction of theamount of catalyst; reduction of the number of steps and improvement ofproduction yield through appropriate choice of an ester; and efficientisolation of an optically active form of a compound for introducing asubstituent by achieving optical resolution using an optically activeacid. Also, the reaction for producing a target compound rapidlyproceeds even though an intermediate have no additional protectivegroup. According to the present invention, a target compound can beproduced at high yield in a simple process.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Results of X-ray structural analysis of the compound produced inReferential Example 6.

BEST MODES FOR CARRYING OUT THE INVENTION

The present invention will hereinafter be described in detail.

The compounds of the invention may be produced through, for example, thefollowing scheme.

Firstly, a compound represented by formula (1):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R² represents an alkoxycarbonyl group which may have asubstituent, an aralkyloxycarbonyl group which may have a substituent,an aliphatic acyl group which may have a substituent, or an aromaticacyl group which may have a substituent; and R³ represents a C1 to C4alkyl group which may have a substituent, an aralkyl group which mayhave a substituent, or a hydrogen atom) (hereinafter a compound may bedenoted along with the number of the formula thereof, for example, theabove compound is denoted by “compound (1)”) can be readily synthesizedthrough the following procedure: reacting a β-keto ester with a1,2-dihalogenoethane (e.g., dibromoethane or dichloroethane) (forproducing a compound in which n is 2, but a dihalgenoalkylene compoundhaving carbon atoms of the number corresponding to n may be generallyemployed) under basic conditions, to thereby form a cyclic keto estercompound; subjecting the keto ester compound to Strecker reaction with,for example, ammonia, a cyanating agent, and an ammonium salt, tothereby form an amino-cyano compound; and protecting the formed aminogroup of the amino-cyano compound. These three steps in the productionmay be performed according to a known method.

The β-keto ester employed in the synthesis of a cyclic keto estercompound is preferably a lower ester of acetoacetic acid; e.g., methylacetoacetate or ethyl acetoacetate. No particular limitation is imposedon the base employed in reaction of a dihalogenoalkylene compound, andany base may be employed so long as the base can be generally used foralkylation of β-keto ester. Examples include sodium carbonate, potassiumcarbonate, and sodium hydroxide. No particular limitation is imposed onthe solvent, and any solvent may be used so long as it does not inhibitreaction.

The amino-cyano compound may be produced through reaction of a cyclicketo ester compound with ammonia and a cyanating agent. Examples of thecyanating agent include cyanides such as sodium cyanide, potassiumcyanide, and tetrabutylammonium cyanide. In the reaction, addition of anammonium salt such as ammonium chloride or ammonium acetate remarkablyaccelerates the reaction. No particular limitation is imposed on thesolvent, and any solvent may be used so long as it does not inhibitreaction.

When a protective group is introduced to the amino-cyano compound, anamino-protecting agent and the amino-cyano compound may be reacted inthe absence of a solvent or in a solvent which does not inhibit thereaction. The protecting agent may be selected in accordance with aprotective group to be introduced. Examples of the protecting agentinclude di-t-butyl dicarbonate, benzyl chloroformate, benzoyl chloride,acetic anhydride, and acetyl chloride.

In the compound represented by formula (1), n is an integer of 2 to 5.Preferably, n is 2.

R¹ represents a C1 to C4 alkyl group which may have a substituent or anaryl group which may have a substituent. When R¹ is an alkyl group, itmay be linear or branched. The alkyl group is preferably methyl, ethyl,propyl, or isopropyl. Of these, methyl and ethyl are preferred, withmethyl being more preferred.

The alkyl group may have one or more substituents selected from thegroup consisting of an amino group, a hydroxyl group, a halogen atom, aC1 to C6 alkylthio group, and a C1 to C6 alkoxy group. The amino groupor hydroxyl group is preferably bound to an end carbon atom. Forexample, aminomethyl, 2-aminoethyl, 2-aminopropyl, 3-aminopropyl,hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and 3-hydroxypropyl arepreferred. When the substituent is a halogen atom, a fluorine atom ispreferred. The substitution degree of fluorine atoms in the substitutedgroup may be monofluoro to perfluoro. Examples include monofluoromethyl,difluoromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl. When thesubstituent is an alkylthio group or an alkoxy group, the substitutedgroup is preferably alkylthiomethyl, alkylthioethyl, alkylthiopropyl,alkoxymethyl, alkoxyethyl, or alkoxypropyl, more preferablymethylthiomethyl, ethylthiomethyl, methylthioethyl, methoxymethyl,ethoxymethyl, or methoxyethyl.

When R¹ is an aryl group, it may be phenyl, tolyl, or naphthyl, withphenyl being preferred. The aryl groups may have one or moresubstituents such as a nitro group, an alkoxy group, an alkyl group, anda halogen atom.

R² represents an alkoxycarbonyl group which may have a substituent, anaralkyloxycarbonyl group which may have a substituent, an aliphatic acylgroup which may have a substituent, or an aromatic acyl group which mayhave a substituent. No particular limitation is imposed on R², and anygroup may be employed so long as it is known as a protective group foran amino group. More preferably, R² is an electron-withdrawingprotective group.

No particular limitation is imposed on the alkoxycarbonyl group whichmay have a substituent, and any such groups may be employed so long asthe alkoxy moiety has 1 to 6 carbon atoms. Examples of the substituentinclude a halogen atom. Examples of the thus-substituted group includet-butyloxycarbonyl and 2,2,2-trichloroethoxycarbonyl.

The aralkyloxycarbonyl group which may have a substituent is preferablyan aralkyl group having a phenyl group, and the alkyl moiety ispreferably methyl. Thus, the aralkyl group is preferably a benzyl group.Examples of the substituent of the aryl moiety in the aralkyl groupinclude an alkyl group, an alkoxy group, a nitro group, and a halogenatom, with methyl, methoxy, chlorine, and nitro being preferred.Examples of the substituent of the alkyl moiety include an alkyl group,with methyl being preferred. Examples of preferred alkoxycarbonyl groupswhich may have a substituent include benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, and p-nitrobenzyloxycarbonyl.

No particular limitation is imposed on the aliphatic acyl group whichmay have a substituent, and any such groups may be employed so long asthe number of carbon atoms is 2 to 7. The acyl group may be linear orbranched. Examples of the substituent include a halogen atom and analkoxy group, with chlorine, fluorine, and methoxy being preferred.Examples of preferred aliphatic acyl groups which may have a substituentinclude acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, andpivaloyl.

The aromatic acyl group which may have a substituent is preferably anacyl group having a phenyl group. Examples of the substituent include analkyl group, an alkoxy group, a nitro group, and a halogen atom, withmethyl, methoxy, chlorine, and nitro being preferred. Specifically, thearomatic acyl group which may have a substituent is preferably a benzoylgroup, a p-nitrobenzoyl group, or a similar group.

Examples of more preferred groups of R² include t-butyloxycarbonyl,benzyloxycarbonyl, benzoyl, and acetyl.

R³ represents a C1 to C4 alkyl group which may have a substituent, anaralkyl group which may have a substituent, or a hydrogen atom. The C1to C4 alkyl group which may have a substituent may be the same asdescribed in relation to R¹. The aralkyl group which may have asubstituent is preferably an aralkyl group having a phenyl group, andthe alkyl moiety is preferably a methyl group. Thus, the aralkyl groupis preferably a benzyl group. Examples of the substituent of the arylmoiety in the aralkyl group include an alkyl group, an alkoxy group, anitro group, and a halogen atom, with methyl, methoxy, chlorine, andnitro being preferred. Examples of the substituent of the alkyl moietyinclude an alkyl group, with methyl being preferred. Specifically, thearalkyl group which may have a substituent is preferably benzyl,p-methoxybenzyl, p-nitrobenzyl, or a similar group. The aralkyl groupmay also a α-methylphenethyl equivalent in which the methyl moiety isfurther substituted by a methyl group.

R³ is preferably a liner short-chain alkyl group, preferably, methyl,ethyl, or propyl, more preferably methyl or ethyl. When R³ is such analkyl group, an aminomethyl group is formed through reduction of thecyano group, concomitant with ring-closure to pyrrolidone.

Compound (2) represented by formula (2):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R² represents an alkoxycarbonyl group which may have asubstituent, an aralkyloxycarbonyl group which may have a substituent,an aliphatic acyl group which may have a substituent, or an aromaticacyl group which may have a substituent) may be produced by treatingcompound (1) in hydrogen gas under atmospheric pressure or pressurized(≦50 atm) conditions in the presence of a metallic catalyst.

In this reaction, firstly, the cyano group is reduced to form anaminomethyl group, and cyclization concomitantly occurs. Examples of themetallic catalyst employed in the step include Raney nickel, Raneycobalt, palladium carbon, platinum carbon, and rhodium carbon. Of these,Raney nickel, Raney cobalt, and rhodium carbon are preferred.

The reaction temperature may be −30 to 170° C., and is preferably 0 to110° C.

The reaction is preferably performed in a solvent. Any solvent may beused so long as it does not inhibit the reaction. Preferably, analcoholic solvent such as methanol or ethanol is employed.

Compound (3) represented by formula (3):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R² represents an alkoxycarbonyl group which may have asubstituent, an aralkyloxycarbonyl group which may have a substituent,an aliphatic acyl group which may have a substituent, or an aromaticacyl group which may have a substituent; and R⁴ represents a benzylgroup, a benzhydryl group, or a trityl group, wherein phenyl groupthereof may have, as a substituent, one or more groups selected from thegroup consisting of a nitro group, an alkoxy group, and a halogen atom)may be produced by R⁴-introduction to the nitrogen atom in the lactamring by reacting compound (2) under basic conditions with an R⁴-formingagent.

Examples of such R⁴-forming agents include benzyl halides such as benzylchloride and benzyl bromide; benzhydryl halides; and trityl halides.

Examples of the base employed in the step include metal alkoxide andsodium hydride.

Any solvent may be used so long as it does not inhibit the reaction.Preferably, an aprotic polar solvent such as dimethylformamide isemployed. The reaction temperature may be −30 to 170° C., and ispreferably 0 to 110° C.

In compound (3), R⁴ represents a benzyl group, a benzhydryl group, or atrityl group. The alkyl group and phenyl group thereof may have one ormore substituents selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom. R⁴ is preferably a benzyl which mayhave substituent or a benzhydryl group which may have a substituent,with benzyl, α-methylbenzyl, and benzhydryl being particularlypreferred.

Compound (4) represented by formula (4):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom) may be produced by removing theprotective group of the amino group of the compound (3). Removal of theprotective group may be performed under known conditions depending onthe type of the protective group introduced to the amino group.

Compound (5) represented by formula (5):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom) may be produced by reducing thecarbonyl group in the amide moiety present as cyclic pyrrolidone in thecompound (4).

Examples of the reducing agent employed in the reduction of the carbonylgroup include aluminum hydride agents such as lithium aluminum hydrideand sodium bis(2-methoxyethoxy)aluminum hydride and boron hydride agentssuch as sodium boron hydride, diborane, and borane-tetrahydrofurancomplex. Any reaction solvent may be employed so long as it does notinhibit the reaction, and ether compounds such as tetrahydrofuran,diethyl ether, dioxane, and dimethoxyethane; and aromatic compounds suchas benzene, toluene, and xylene are preferred. The reaction temperaturemay be −30 to 170° C., and is preferably 0 to 110° C.

Since R² present in compound (3) is a protective group containing acarbonyl group, this must be removed in consideration of thecharacteristics of the reducing agent used for conversion to compound(5).

Therefore, if R² does not change in the reduction step, this removal maybe omitted.

The carbon atom in compound (5) to which a ring amino group has beenbound is an asymmetric carbon atom. Therefore, compound (5) includes twoantipodal isomers, which are represented by formulas (5-1) and (5-2).

The compound represented by formula (5-1) or (5-2) may be produced bytreating compound (5) (racemic mixture) with an optically activecarboxylic acid or an optically active sulfonic acid in an organicsolvent, to thereby form crystals of an amine salt of the opticallyactive acid. Thus, each optically active form can be isolated throughracemic resolution. Examples of the optically active acid employable inracemic resolution include carboxylic acids such as mandelic acid, malicacid, lactic acid, and tartaric acid; and sulfonic acids such ascamphorsulfonic acid. Of these, mandelic acid is particularly preferred.

The amount of mandelic acid employed in racemic resolution may be 1 to1.2 equivalents with respect to the optical isomer which is contained inthe racemic mixture and is to be isolated. Examples of the solventemployed in the racemic resolution include aromatic compounds such asbenzene, toluene, and xylene; ether compounds such as tetrahydrofuran,diethyl ether, dioxane, and dimethoxyethane; haloaliphatic hydrocarbonsolvents such as methylene chloride and chloroform; aliphatichydrocarbon solvents such as hexane and heptane; and ketonic solventssuch as acetone and methyl ethyl ketone. Of these, aromatic compoundssuch as benzene, toluene, and xylene are preferred, with toluene beingparticularly preferred. Crystallization temperature is −40° C. to 30°C., preferably −20° C. to 0° C. Notably, these conditions may be appliednot only to mandelic acid but also to other optically active acids.

After a target antipode has been isolated as an optically active acidsalt, an amine salt of the opposite stereoisomer of compound (5) can beproduced by treating the filtrate with a base such as aqueous sodiumhydroxide to thereby remove the optically active acid and adding anoptically active acid having an opposite stereoproperty to the solutionfor crystallization. Furthermore, by treating the filtrate obtained inthe second crystallization with aqueous sodium hydroxide or the like tothereby remove carboxylic acid and adding the first optically activeacid, an amine salt of the optically active acid can further beisolated.

Mandelic acid is a suitable optically active acid for optical resolutionof compound (5) in which R⁴ is benzyl, R¹ is methyl, and n is 2, and thecompounds isolated through racemic resolution by use of mandelic acidare the following compounds.

These compounds may be a hydrate thereof.

Free-form compound (5-1) or (5-2) can be recovered without lowering itsoptical purity through the following procedure: treating the thus-formedsalt of the optically active carboxylic acid or sulfonic acid with anaqueous alkaline solution such as an aqueous inorganic base solution(e.g., aqueous sodium hydroxide, aqueous potassium hydroxide, aqueousammonia, or aqueous sodium bicarbonate), or an aqueous organic basesolution (e.g., a metal alkoxide dissolved in water) and extracting withan organic solvent which is not miscible with water such as ahydrocarbon solvent (e.g., hexane or heptane), an aromatic hydrocarbonsolvent (e.g., benzene or toluene), a halo-hydrocarbon solvent (e.g.,methylene chloride and chloroform), or ethyl acetate.

Compound (6) represented by formula (6):

(n is an integer of 2 to 5; and R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent) or an optically active form thereof may be produced byremoving the protective group present in the amino group in thepyrrolidine ring of compound (5) or an optically active form thereof.Removal of the protective group may be performed under known conditionsdepending on the type of the protective group present in the aminogroup. The protective group present in the amino group in thepyrrolidine ring of compound (5) is preferably a benzyl-based group fromthe viewpoint of easiness for the removal. Thus, compound (5) ispreferably a compound (51) represented by formula (51):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁴¹ represents a benzyl group or a benzhydryl group,wherein phenyl group thereof may have, as a substituent, one or moregroups selected from the group consisting of a nitro group, an alkoxygroup, and a halogen atom) or an optically active form thereof. In otherwords, when this compound (51) is employed, hydrogenolysis readilyproceeds in the presence of a metallic catalyst and in the presence ofhydrogen gas or formic acid or a salt thereof as a hydrogen source, tothereby attain deprotection. In deprotection, when hydrochloric acid,hydrogen chloride dissolved in organic solvent, or the like is added toacidify the medium, reaction readily proceeds, whereby compound (6) oran optically active form thereof can be produced as a salt of the addedacid.

Examples of the metallic catalyst employed in the deprotection includeRaney nickel, Raney cobalt, palladium carbon, platinum carbon, andrhodium carbon. Of these, palladium carbon is preferred.

When hydrogen gas is employed, the pressure at the reaction ispreferably 1 to 50 atm. When formic acid or its salt is employed as ahydrogen source, ambient pressure may be employed. Any solvent may beused in the reaction so long as the solvent does not inhibit thereaction, and an alcoholic solvent such as methanol or ethanol ispreferred. The reaction can be accelerated through addition of acid tothe reaction mixture. Examples of the acid include inorganic acids suchas hydrochloric acid, hydrogen chloride dissolved in organic solvent,and sulfuric acid; and organic acids such as formic acid, acetic acid,and p-toluenesulfonic acid. Of these, hydrochloric acid and hydrogenchloride dissolved in organic solvent are preferred. The amount of acidis adjusted to 2 to 100 equivalents with respect to the substrate fromthe viewpoint of efficiency. An amount of 3 to 20 equivalents areparticularly effective. In this deprotection process, stereoproperty iscompletely retained.

When compound represented by formula (6-1):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent) or a salt thereof is reacted with a boron-chelate of aquinolone-skeleton compound represented by the following formula:

(R⁶ represents a hydrogen atom or a fluorine atom; R⁷ represents anamino group which may have a substituent, a C1 to C4 alkoxy group whichmay have a substituent, a hydrogen atom, or a hydroxyl group; and Xrepresents a leaving group) in the presence of a base, a compoundrepresented by formula (9-1):

(wherein n, R¹, R⁶, and R⁷ are the same as defined above) can beproduced.

The base employed in the above reaction may be an organic base or aninorganic base. Preferably, a tertiary amine as an organic amine isused. The reaction is performed in a polar solvent. Examples of thesolvent include ester solvents such as ethyl acetate; amide solventssuch as dimethylformamide and dimethylacetamide; acetonitrile; alcoholicsolvents such as benzyl alcohol; dimethylsulfoxide; dioxolan; and1,3-dimethyl-2-imidazolidinone. Of these, amide solvents(dimethylformamide and dimethylacetamide) are preferred. Examples of thetertiary amines employed in the reaction include trimethylamine,triethylamine, N-methylpiperidine, N-methylmorpholine, and pyridine. Thereaction temperature is −20° C. to 150° C., preferably 0 to 100° C.

In the boron-chelate of a quinolone-skeleton compound, X represents aleaving group. Examples of the leaving group include a halogen atom anda substituted sulfonyloxy group. The leaving group is preferably ahalogen atom, particularly a fluorine atom.

Compound represented by formula (10-1) can be produced through removinga boron-chelate moiety from a boron-chelate compound such as compoundrepresented by formula (9-1). The removing process may be performedunder basic or acidic conditions in the presence of water or a proticsolvent. Depending on the employed removal conditions; i.e., basic oracidic, the compound represented by formula (10-1) may be formed as ahydrate or a salt thereof. Examples of the solvent employed forde-chelation include alcoholic solvents such as methanol, ethanol, andisopropyl alcohol; halogen-containing solvents such as chloroform; estersolvents such as ethyl acetate; and acetonitrile. Of these, alcoholicsolvents such as ethanol and isopropyl alcohol are preferred. Thereaction temperature is −20° C. to 150° C., preferably 0 to 100° C.Examples of the basic reagent include amine reagents such astriethylamine and pyridine; and alkali metal reagents such as sodiumhydroxide and potassium hydroxide. Acidic conditions may be realized byuse of an organic acid such as acetic acid, oxalic acid, or sulfonicacid; or an inorganic acid such as hydrochloric acid, sulfuric acid, ornitric acid.

Compound (7) represented by formula (7):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R⁴ represents a benzyl group, a benzhydryl group, or atrityl group, wherein phenyl group thereof may have, as a substituent,one or more groups selected from the group consisting of a nitro group,an alkoxy group, and a halogen atom; and R⁵ represents at-butyloxycarbonyl group, a benzyloxycarbonyl group, a benzoyl group, oran acetyl group) or an optically active form thereof may be producedthrough introducing a protective group to the primary amino group in thering of compound (5) represented by formula (5):

or an optically active form thereof. Examples of the protecting agentemployed for introducing a protective group include di-t-butyldicarbonate, benzoyl chloride, acetic anhydride, and acetyl chloride.

The protective group R⁴ attached to the amino group of the ring of thecompound (7) may be removed under a known removal conditions dependingon the type of the protective group. For example, when the protectivegroup is a benzyl-type protective group, the group is removed throughhydrogenolysis using hydrogen gas, formic acid, or a salt thereof, as ahydrogen source, in the presence of a metallic catalyst, wherebycompound (8) represented by formula (8):

(wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; and R⁵ represents a t-butyloxycarbonyl group, abenzyloxycarbonyl group, a benzoyl group, or an acetyl group) or anoptically active form thereof can be produced. The removal reaction isperformed in the presence of a metallic catalyst. Examples of such ametallic catalyst include Raney nickel, Raney cobalt, palladium carbon,platinum carbon, and rhodium carbon. Of these, palladium carbon ispreferred. When hydrogen gas is used, the pressure during reaction ispreferably 1 to 50 atm. When formic acid or a salt thereof is used as ahydrogen source, ambient pressure may be employed. Any solvent may beused so long as it does not impede the reaction. In this deprotectionprocess, stereoproperty is completely retained.

EXAMPLES

The present invention will hereinafter be described in detail by way ofexamples, which should not be construed as limiting the inventionthereto.

Example 1 1-[(1-Amino-1-cyano)ethyl]-1-ethoxycarbonylcyclopropane

To a solution of 1-acetyl-1-ethoxycarbonylcyclopropane (279 g) inethanol (1.4 L), 28% aqueous ammonia (1.4 L), ammonium chloride (478 g)and sodium cyanide (175 g) were added, and the mixture was stirred atroom temperature for 16 hours. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The solvent of the extractwas evaporated under reduced pressure. After concentration of theextract, insoluble material was precipitated. Thus, the residue wasdiluted again with ethyl acetate and the insoluble material was removedthrough filtration. The solvent of the filtrate was evaporated underreduced pressure, to thereby yield the title product as brown oil (353g, purity: 72.0%, yield: 78.2%).

Brown oil;

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.10-1.36 (m, 4H), 1.19 (t, J=6.8 Hz,3H), 1.51 (s, 3H), 2.14 (brs, 2H), 4.18 (q, J=6.8 Hz, 2H).

Example 21-[(1-t-Butoxycarbonylamino-1-cyano)ethyl]-1-ethoxycarbonylcyclopropane

Di-t-butyl dicarbonate (25.1 g) was added to1-[(1-amino-1-cyano)ethyl]-1-ethoxycarbonylcyclopropane (21.7 g, purity:80.2%), and the mixture was stirred at an external temperature of 100°C. for 6 hours. The reaction mixture was cooled to room temperature, and7N ammonia-methanol solution (4.1 mL) was added to the cooled mixture,followed by stirring for 10 minutes. The solvent was evaporated underreduced pressure, to thereby yield a crude product of the title compoundas brown solid. The crude product can be purified through silica gelcolumn chromatography (hexane ethyl acetate).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.19-1.26 (m, 1H), 1.25 (t, J=6.8 Hz,3H), 1.34-1.48 (m, 2H), 1.47 (s, 9H), 1.55-1.60 (m, 1H), 1.88 (s, 3H),4.15 (q, J=6.8 Hz, 2H) 5.70 (brs, 1H).

Example 3 1-[(1-Benzoylamino-1-cyano)ethyl]-1-ethoxycarbonylcyclopropane

1-[(1-Amino-1-cyano)ethyl]-1-ethoxycarbonylcyclopropane (1.91 g, purity:91.5%) was dissolved in acetonitrile (19 mL), and triethylamine (2.92mL) and benzoyl chloride (2.43 mL) were added to the solution, followedby stirring at room temperature for 1 hour. After completion ofreaction, water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was dried over sodiumsulfate anhydrate. The solvent of the organic layer was evaporated underreduced pressure, and the residue was purified through silica gel columnchromatography (hexane:ethyl acetate), to thereby yield the titleproduct as white crystals (2.08 g, yield: 75.6%).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.25 (t, J=6.8 Hz, 3H), 1.30-1.36 (m,1H), 1.40-1.44 (m, 1H), 1.52-1.58 (m, 1H), 1.75-1.80 (m, 1H), 2.00 (s,3H), 4.15 (m, 2H), 7.43 (t, J=7.2 Hz, 2H), 7.54 (t, J=7.2 Hz, 1H), 7.81(d, J=7.2 Hz, 2H).

Example 4 7-t-Butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane

Raney nickel (17.4 mL) was added to a solution of crude1-[(1-t-butoxycarbonylamino-1-cyano)ethyl]-1-ethoxycarbonylcyclopropanein methanol (348 mL). A reaction vessel was purged with hydrogen gas.The reaction mixture was placed in the reaction vessel, followed bystirring at an external temperature of 55° C. for 20 hours. Then, thereaction vessel was purged with nitrogen, and insoluble material wasremoved through filtration, followed by washing with methanol. Thefiltrate and the washings were combined, and the solvent of the mixturewas evaporated under reduced pressure. Subsequently, isopropyl ether mL)was added to the residue, followed by stirring for 30 minutes. Thethus-precipitated crystals were collected and dried under reducedpressure, to thereby yield the title product as white crystals (9.99 g).

¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 0.65-0.84 (m, 4H), 1.17 (s, 3H), 1.37(s, 9H), 3.11 (d, J=9.6 Hz, 1H), 4.11 (brd, J=9.6 Hz, 1H), 6.60 (brs,1H), 7.59 (brs, 1H).

Example 5 7-t-Butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane

Di-t-butyl dicarbonate (17.9 g) was added to1-[(1-amino-1-cyano)ethyl]-1-ethoxycarbonylcyclopropane (16.0 g, purity:72.0%), and the mixture was stirred at an external temperature of 100°C. for 6 hours. The reaction mixture was cooled to room temperature, and7N ammonia-methanol solution (4.5 mL) was added to the cooled mixture,followed by stirring for 10 minutes. Subsequently, the solvent of thereaction mixture was evaporated under reduced pressure, to thereby yieldcrude1-[(1-t-butoxycarbonylamino-1-cyano)ethyl]-1-ethoxycarbonylcyclopropane(19.23 g) as brown oil (gradually solidified). Subsequently, 5% rhodiumcarbon (5.06 g) was added to a solution of the crude product (18.68 g)in methanol (202 mL). A reaction vessel was purged with hydrogen gas,and the reaction mixture placed in the reaction vessel was stirred at anexternal temperature of 55° C. for 38 hours. Then, the reaction vesselwas purged with nitrogen gas, and methanol (260 mL) was added to thereaction mixture placed in the reaction vessel. The reaction mixture wasstirred at an external temperature of 55° C. for 1 hour, and insolublematerial was removed through filtration. The solvent of the filtrate wasevaporated under reduced pressure, and isopropyl ether (348 mL) wasadded to the residue, followed by stirring for 30 minutes. Theprecipitated crystals were collected through filtration, and dried underreduced pressure, to thereby yield the title product as white crystals(9.99 g, yield: 74.9% with respect to1-[(1-amino-1-cyano)ethyl]-1-ethoxycarbonylcyclopropane).

Example 6 7-Benzoylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane

1-[(1-Benzoylamino-1-cyano)ethyl]-1-ethoxycarbonylcyclopropane (1.00 g,3.49 mmol) was dissolved in ethanol, and Raney nickel (10 mL) was addedto the solution, followed by stirring in a hydrogen gas atmosphere atroom temperature. After four hours, insoluble material was removedthrough filtration, and the filtrate was concentrated under reducedpressure, to thereby yield the title product as crude white crystals(756 mg, yield: 88.6%).

¹H-NMR (400 MHz, CD₃OD) δ ppm: 0.86-0.99 (m, 2H), 1.06-1.12 (m, 2H),1.43 (s, 3H), 3.41 (d, J=10.2 Hz, 1H), 4.11 (d, J=10.2 Hz, 1H), 7.43 (t,J=6.8 Hz, 2H), 7.49 (t, J=6.8 Hz, 1H), 7.74 (d, J=6.8 Hz, 2H).

Example 75-Benzyl-7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane

7-t-Butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane (42.63 g)was suspended in dimethylformamide (850 mL) under a nitrogen gasatmosphere, and the suspension was cooled with ice. To the suspension,60% sodium hydride (6.93 g) was added, and the mixture was returned toroom temperature. Subsequently, benzyl bromide (22.64 mL) was added tothe reaction mixture, followed by stirring. After three hours, insolublematerial was removed through filtration, and water was added to thefiltrate. Ethyl acetate was further added thereto for extraction. Theorganic layer obtained through extraction was dried with sodium sulfate,followed by filtration. The filtrate was concentrated under reducedpressure, to thereby yield an oily residue. The residue was subjected tosilica gel chromatography (hexane:ethyl acetate), to thereby yield thetitle product as pale yellow oil (51.0 g, yield: 89.2%).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.77-0.81 (m, 1H), 0.92-1.05 (m, 2H),1.22 (s, 3H), 1.20-1.26 (m, 1H), 1.37 (s, 9H), 3.14 (d, J=10.4 Hz, 1H),3.98 (brd, J=10.4 Hz, 1H), 4.43 (d, J=14.8 Hz, 1H), 4.56 (d, J=14.8 Hz,1H), 4.57 (brs, 1H), 7.22-7.34 (m, 5H).

Example 8 7-Amino-5-benzyl-4-oxo-7-methyl-5-azaspiro[2.4]heptane

5-Benzyl-7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane(43.63 g) was dissolved in toluene, and the solution was stirred underice-cooling. 37% Concentrated hydrochloric acid (100 mL) was addeddropwise thereto, followed by stirring. After 0.5 hours, water was addedto the reaction mixture. The mixture was stirred and left to stand so asto separate the aqueous layer from the organic layer. Sodium hydroxide(54 g) was added to and dissolved in the separated aqueous layer so asto alkalify the layer. The aqueous layer was extracted several timeswith toluene repeatedly. All the toluene layers were combined and washedwith saturated brine. The washed toluene layer was dried with sodiumsulfate, followed by filtration. The filtrate was concentrated underreduced pressure, to thereby yield the title product (21.29 g, yield:90.2%).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.72-0.84 (m, 2H), 0.99-1.13 (m, 2H),1.06 (s, 3H), 3.11 (d, J=9.6 Hz, 1H), 3.22 (d, J=9.6 Hz, 1H), 4.48 (d,J=15.2 Hz, 1H), 4.52 (d, J=15.2 Hz, 1H), 7.21-7.38 (m, 5H).

Example 9 7-Amino-5-benzyl-4-oxo-7-methyl-5-azaspiro[2.4]heptane

A suspension of7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane (10.0 g,41.6 mmol) in dimethylacetamide (100 mL) was cooled with ice, andt-butoxy potassium (4.67 g, 1.0 eq.) and benzyl chloride (5.27 mL, 1.1eq.) were added thereto. The reaction mixture was returned to roomtemperature, followed by stirring for 2 hours. Thereafter, water wasadded to the mixture, followed by extraction with toluene. The solventof the extract was evaporated under reduced pressure, to thereby yield5-benzyl-7-t-butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptaneas a crude product. The crude product was dissolved in toluene (100 mL),and methanesulfonic acid (2.97 mL) was added to the solution, followedby stirring under reflux for 2 hours. The reaction mixture was cooled toroom temperature. Water was added to the cooled mixture for extraction,and the formed organic layer was removed. Aqueous sodium hydroxidesolution (5N) was added to the remaining aqueous layer so as to alkalifythe layer, followed by extraction with toluene. The solvent of theextract was evaporated under reduced pressure, to thereby yield thetitle product as a pale brown solid (8.63 g, yield: 90.1%).

Example 10 7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane

7-Amino-5-benzyl-4-oxo-7-methyl-5-azaspiro[2.4]heptane (27 g) wasdissolved in anhydrous tetrahydrofuran (265 mL) in an argon atmosphere,and the solution was cooled with ice. Lithium aluminum hydride (13.3 g)was added thereto, and the mixture was returned to room temperature.After disappearance of the starting materials had been confirmed, thereaction mixture was cooled with ice. Water (200 mL) and 28% aqueoussodium hydroxide solution (70 mL) were added to cooled mixture, followedby stirring. Toluene was added to the mixture for extraction to separatethe organic layer, and the organic layer was washed with saturatedbrine, followed by drying with sodium sulfate. The desiccant was removedthrough filtration, and the filtrate was concentrated under reducedpressure, to thereby yield the title product (24.7 g, yield: 98.6%).

Pale yellow oil;

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.36-0.45 (m, 2H), 0.53-0.66 (m, 2H),0.95 (s, 3H), 1.40 (brs, 2H), 2.47 (d, J=9.2 Hz, 1H), 2.55 (d, J=9.2 Hz,1H), 2.74 (dd, J=9.2, 1.2 Hz, 2H), 3.58 (d, J=13.2 Hz, 1H), 3.62 (d,J=13.2 Hz, 1H), 7.21-7.39 (m, 5H).

Example 11 7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane

A solution (65% toluene solution) of sodium bis(2-methoxyethoxy)aluminumhydride (1.65 kg, 3.5 eq.) in toluene (870 mL) was added to a solutionof 7-amino-5-benzyl-4-oxo-7-methyl-5-azaspiro[2.4]heptane (348 g, 1.51mmol) in toluene (2.62 L), and the mixture was stirred at an internaltemperature of 60° C. for 1 hour. The reaction mixture was cooled withice. Aqueous sodium hydroxide solution (5N) was added to the cooledmixture, and the aqueous layer was extracted with toluene. Thethus-obtained organic layers were combined, and the solvent of thecombined organic layer was evaporated under reduced pressure, to therebyyield the title product as brown oil (343 g, purity: 81.3%, yield:100%).

Example 12 (−)-7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptaneD-mandelate

D-Mandelic acid (111 g) was added to a solution of7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (325 g, purity: 81.3%,1.22 mol) in toluene (4.8 L), and seed crystals for the title compoundwere added to the mixture, followed by stirring overnight (for 20 hours)at an internal temperature of −9° C. The precipitated crystals werecollected through filtration, followed by washing twice with coldtoluene (400 mL) and drying under reduced pressure, to thereby yield thetitle product as white crystals (117 g, yield: 26.0%, optical purity:99.2% e.e.). Optical purity of the product was determined through HPLC.Specifically, the mandelate (about 10 mg) was sampled, and 10% aqueoussodium hydroxide (0.3 mL) and hexane (0.3 mL) were added to the sampledmandelate. After stirring, the mixture was left to stand, and the hexanelayer was analyzed through HPLC. The ¹H-NMR spectral data given belowwere obtained from the free form of the product.

HPLC Conditions:

Column: DAICEL CHIRALPAK OD-H, 0.46×150 mm

Column temperature: 30° C.

Mobile phase: n-hexane:isopropyl alcohol=95:5, flow rate: 1.0 mL/min

Wavelength: 254 nm, (−) form: 8.7 min, (+) form: 7.4 min

The peak at 8.7 min is, among others, a predominant peak and isattributed to an antipode obtained through racemic resolution withD-mandelic acid.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.32-0.38 (m, 1H), 0.44-0.50 (m, 1H),0.60-0.66 (m, 1H), 0.79-0.85 (m, 1H), 0.91 (s, 3H), 2.41-2.46 (m, 2H),2.82 (d, J=9.2 Hz, 1H), 2.99 (d, J=9.2 Hz, 1H), 3.57 (d, J=12.8 Hz, 2H),3.71 (d, J=12.8 Hz, 1H), 4.67 (brs, 1H), 4.86 (s, 1H), 7.16-7.42 (m,10H). Optical rotation [α]_(D)=−69.9° (c=1.0, MeOH)

Example 13 (−)-7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptaneD-(−)-mandelate

Toluene (11.5 L) was added to a solution (1,660 mL) of7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (2,202 g, purity: 35%)in toluene, and D-mandelic acid (325.2 g) was added to the mixture,followed by cooling. Seed crystals for the title compound were added tothe cooled mixture, followed by stirring overnight at an internaltemperature of −10° C. The precipitated crystals were collected throughfiltration and washed twice with cold toluene, followed by drying underreduced pressure. The thus-obtained crude products (first crudecrystals) were suspended under stirring in toluene (2.2 L) at roomtemperature. After 2.5 hours, the suspension was filtered so as tocollect crystals. The collected crystals were washed with cold toluene,followed by drying under reduced pressure, to thereby yield the titleproduct as white crystals (first crystals) (365.4 g, yield: 27.1%,optical purity: 97.4% e.e.).

To the toluene-containing filtrate remaining after first crude crystalshad been collected, 10% aqueous sodium hydroxide was added, and themixture was stirred at room temperature, followed by separation of theorganic layer. In addition, saturated brine was added to the organiclayer so as to separate another organic layer, followed by drying withsodium sulfate. The desiccant was removed through filtration, and thefiltrate was concentrated under reduced pressure. Subsequently, toluene(13.5 L) was added to the concentration residue, and L-mandelic acid(297.5 g) was added to the mixture, followed by cooling. Seed crystalsfor the title compound were added to the cooled mixture, and the mixturewas stirred overnight at an internal temperature of −8° C. Theprecipitated crystals were collected through filtration, to therebyyield (+)-7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane L-mandelate(512.7 g, optical purity: 97.0% e.e.). Thereafter, the mother liquid wasconcentrated to form a residue (542.7 g). Toluene (4.9 L) was added tothe residue, and D-mandelic acid (125 g) was added to the mixture,followed by cooling. Seed crystal for the title compound was added tothe cooled mixture, and the mixture was stirred overnight at an internaltemperature of −9° C. The precipitated crystals were collected throughfiltration and washed with cold toluene. In addition, the washedcrystals were suspended under stirring in hexane (600 mL) at roomtemperature. After 2.5 hours, the suspension was filtered. The collectedcrystals were dried under reduced pressure, to thereby yield the titleproduct as white crystals (second crystals) (185.5 g, yield: 13.7%,optical purity: 97.4% e.e.).

(+)-7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane L-mandelate

A free-form amine was produced from the thus-obtained salt and wassubjected to ¹H-NMR measurement. The spectrum of the amine was found tocoincide with that of the free-form compound of Example 12.

White powdery crystals;

Optical rotation [α]_(D)=+65.6° (c=1.0, MeOH)

Example 14 (−)-7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane

To (−)-7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane D-mandelate(22.43 g, optical purity: 98% e.e.), 10% Aqueous sodium hydroxide andtoluene were added, and the mixture was stirred at room temperature.Thereafter, the toluene layer was separated, washed with saturatedbrine, and dried with sodium sulfate. The desiccant was removed throughfiltration, and the filtrate was concentrated under reduced pressure, tothereby yield the title product as pale yellow oil (16.13 g, opticalpurity: 98% e.e.).

Pale yellow oil;

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.36-0.45 (m, 2H), 0.53-0.66 (m, 2H) 0.95(s, 3H), 1.43 (brs, 2H), 2.47 (d, J=9.2 Hz, 1H), 2.55 (d, J=9.2 Hz, 1H),2.735 (d, J=9.2 Hz, 1H), 2.740 (d, J=9.2 Hz, 1H), 3.58 (d, J=13.2 Hz,1H), 3.62 (d, J=13.2 Hz, 1H), 7.21-7.39 (m, 5H)

Optical rotation [α]_(D)=−25.6° (c=1.1, MeOH)

Example 15 (+)-7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane

(+)-7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane L-mandelate (6.16g, optical purity: 96% e.e.) was processed in a manner similar to thatemployed in Example 14, to thereby form a target product (7.99 g,purity: 47%, optical purity: 96% e.e.) as pale yellow oil. ¹H-NMR dataof the product were found to coincide with those obtained in Example 14.

Optical rotation [α]_(D)=+22.1° (c=1.1, MeOH)

Example 16 (−)-7-Amino-7-methyl-5-azaspiro[2.4]heptane dihydrochloride

Methanol (91 mL) was added to(−)-7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (16.2 g) fordissolution. To the solution, 5% palladium carbon (5.33 g, watercontent: 50%) and concentrated hydrochloric acid (15.8 mL) were added. Areaction vessel was purged with hydrogen gas, and the mixture placed inthe reaction vessel was stirred for 13 hours. The catalyst was removedthrough filtration and washing with ethanol. All the organic layers werecombined and concentrated under reduced pressure. Ethanol and isopropylalcohol were added to the residue, and the mixture was concentratedunder reduced pressure several times under azeotropic conditions. Afterazeotropy, isopropyl alcohol was added to the residue, and the mixturewas stirred at room temperature so as to precipitate crystals. Thecrystals were collected through filtration and dried under reducedpressure, to thereby yield first crystals of the title compound (9.75 g,yield: 80%). Through elemental analysis, the obtained first crystalswere found to be a dihydrochloride salt. To another residue obtainedthrough concentration of the filtrate, methanol and isopropyl alcoholwere added, and the mixture was cooled so as to precipitate crystals.The crystals were collected through filtration and dried under reducedpressure, to thereby yield second crystals of the title compound (1.41g, yield: 12%).

¹H-NMR (400 MHz, D₂O) δ ppm: 0.73-0.78 (m, 1H), 0.89-1.01 (m, 3H), 1.40(s, 3H), 3.25 (d, J=12.8 Hz, 1H), 3.61 (d, J=12.8 Hz, 1H), 3.62 (d,J=13.6 Hz, 1H), 3.74 (d, J=13.6 Hz, 1H).

Elemental analysis: as C₇H₁₄N₂.2HCl;

Calculated: C, 42.22; H, 8.10; N, 14.07; Cl, 35.61.

Found: C, 41.92; H, 8.27; N, 13.79; Cl, 35.21.

Optical rotation [α]_(D)=−11° (c=1.0, H₂O)

Example 17 (−)-7-Amino-7-methyl-5-azaspiro[2.4]heptane dihydrochloride

To a solution of (−)-7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptaneD-(−)-mandelate (94.0 g, 255 mmol) in toluene (940 mL), 1N aqueoussodium hydroxide (470 mL) was added, and the mixture was stirred for 10minutes. The toluene layer was separated and concentrated under reducedpressure. The residue was dissolved in methanol (940 mL), andconcentrated hydrochloric acid (64 mL) and 5% palladium carbon (9.40 g)were added to the solution. A reaction vessel was purged with hydrogengas, and the reaction mixture placed in the reaction vessel was stirredat room temperature for 19 hours. After completion of reaction, thereaction mixture was filtered through Celite so as to remove insolublematerial, followed by washing twice with methanol. The filtrate and thewashings were combined, and the solvent of the mixture was evaporatedunder reduced pressure. Thereafter, isopropyl alcohol was added to theresidue, and the mixture was stirred overnight at room temperature andfurther stirred for 2 hours with ice-cooling. The precipitated crystalswere collected through filtration and washed with cold isopropylalcohol, followed by drying under reduced pressure, to thereby yieldfirst crystals of the title compound as pale brown crystals (47.3 g,yield: 93.0%). Second crystals of the title compound (1.37 g, 2.7%) werealso collected from the filtrate.

Example 18 (+)-7-Amino-7-methyl-5-azaspiro[2.4]heptane dihydrochloride

(+)-7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (2.1 g, opticalpurity: 98% e.e.) was processed in a manner similar to that employed inExample 16, to thereby form a target product (1.09 g). ¹H-NMR data ofthe product were found to coincide with those obtained in Example 16.

Optical rotation [α]_(D)=+11.2° (c=1.0, H₂O)

Example 195-Benzyl-7-t-butoxycarbonylamino-7-methyl-5-azaspiro[2.4]heptane

7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (7.3 g) was dissolvedin toluene (30 mL) t-Butyl dicarbonate (9.3 mL) and 1N aqueous sodiumhydroxide (10 mL) were added to the solution, followed by stirring for15 hours at room temperature and then for 4 hours at 50° C. Aftercompletion of reaction, the toluene layer was separated and washed withwater, followed by drying with sodium sulfate. The desiccant was removedthrough filtration, and the filtrate was concentrated under reducedpressure. The residue was purified through silica gel chromatography(hexane:ethyl acetate), to thereby yield the title product (8.745 g,yield: 82%). Notably, when optically active7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane is treated inaccordance with the above-described procedure, the correspondingoptically active target product can be yielded without decreasingoptical purity.

White crystals;

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.41-0.45 (m, 1H), 0.50-0.55 (m, 1H),0.64-0.69 (m, 1H), 0.80-0.85 (m, 1H), 1.20 (s, 3H), 1.43 (s, 9H), 2.43(d, J=9.2 Hz, 1H), 2.58 (d, J=9.6 Hz, 1H), 2.83 (d, J=9.2 Hz, 1H), 3.32(d, J=9.6 Hz, 1H), 3.57 (d, J=13.2 Hz, 1H), 3.68 (d, J=13.2 Hz, 1H),4.75 (brs, 1H), 7.22-7.38 (m, 5H).

Example 20 (−)-7-t-Butoxycarbonylamino-7-methyl-5-azaspiro[2.4]heptane

(−)-7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane D-mandelate (5.99g) was dissolved in toluene (60 mL). To the solution, 5N Aqueous sodiumhydroxide (60 mL) was added, and the mixture was stirred at roomtemperature, followed by separation of the toluene layer. Toluene wasalso added to the remaining aqueous layer for extraction. All thetoluene layers were combined, and t-butyl dicarbonate (19.0 mL) wasadded to the combined toluene layer, followed by stirring at roomtemperature for 2 hours. After completion of reaction, 10% aqueouscitric acid was added to the reaction mixture, to thereby extract theaqueous citric acid layer. Separately, 10% aqueous citric acid was addedto the remaining toluene layer, to thereby separate another aqueouscitric acid layer. Thereafter, all the aqueous layers were combined, andthe combined aqueous layer was alkalified with 5N aqueous sodiumhydroxide (30 mL). Subsequently, toluene was added to the alkalifiedaqueous layer so as to extract the organic layer, and the solvent of theorganic layer obtained through extraction was evaporated under reducedpressure. Methanol (60.0 mL) was added to the residue, and 5% palladiumcarbon (0.59 g, water content: 50%) was added to the mixture, followedby stirring at room temperature in a hydrogen atmosphere. After 14hours, 5% palladium carbon was removed through filtration. The filtratewas concentrated under reduced pressure, to thereby yield the titleproduct (3.576 g, yield: 97%). This product can be purified throughrecrystallization from a solvent such as hexane, heptane, oracetonitrile, or formation of a crystalline salt with, for example,oxalic acid.

White crystals;

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.39-0.44 (m, 1H), 0.57-0.61 (m, 2H),0.76-0.81 (m, 1H), 1.10 (s, 3H), 1.44 (s, 9H), 1.87 (br s, 1H), 2.77 (d,J=12.0 Hz, 1H), 2.78 (d, J=11.2 Hz, 1H), 3.14 (d, j=11.2 Hz, 1H), 3.70(br d, J=12.0 Hz, 1H), 4.46 (br s, 1H).

Optical rotation [α]_(D)=−70.1° (c=1.0, MeOH)

Example 217-[(7S)-7-Amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-8-methoxy-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid-BF₂ complex

6,7-Difluoro-8-methoxy-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid-BF₂ complex (7.2 g) was dissolved in dimethylacetamide (22 mL).(−)-7-Amino-7-methyl-5-azaspiro[2.4]heptane dihydrochloride (4.8 g) andtriethylamine (9.45 mL) were added to the solution, followed by stirringat 30° C. The reaction mixture was stirred overnight (for 18 hours), andwater was added to the reaction mixture. The precipitated crystals werecollected through filtration and dried, to thereby yield the titleproduct as yellow crystals (8.25 g, yield: 89%).

¹H-NMR (400 MHz, CD₃OD) δ ppm: 0.56-0.64 (m, 2H), 0.79-0.90 (m, 2H),1.20 (s, 3H), 1.65-1.78 (m, 2H), 3.68 (s, 3H), 3.80-3.94 (m, 4H),4.31-4.38 (m, 1H), 5.00 (dm, J=65.6 Hz, 1H), 7.86 (d, J=14.0, 1H), 9.08(d, J=2.0 Hz, 1H).

Example 227-[(7R)-7-Amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-8-methoxy-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid-BF₂ complex

6,7-Difluoro-8-methoxy-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid-BF₂ complex (1.19 g) was dissolved in dimethylacetamide (3.6 mL).(+)-7-Amino-7-methyl-5-azaspiro[2.4]heptane dihydrochloride (0.72 g) andtriethylamine (1.47 mL) were added to the solution, followed by stirringat 35° C. for 4 hours. The reaction mixture was further stirred at roomtemperature overnight (for 18 hours), and water was added thereto. Theprecipitated crystals were collected through filtration and dried, tothereby yield the title product as yellow crystals (1.31 g, yield:85.0%).

¹H-NMR (400 MHz, DMSO-D₆) δ ppm: 0.41-0.64 (m, 3H), 0.75-0.83 (m, 1H),1.10 (s, 3H), 1.53-1.82 (m, 2H), 3.60 (s, 3H), 3.67-3.85 (m, 4H),4.29-4.36 (m, 1H), 5.09 (dm, J=64.0 Hz, 1H), 7.83 (d, J=14.0, 1H), 9.00(d, J=2.4 Hz, 1H).

Example 237-[(7S)-7-Amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-8-methoxy-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Isopropyl alcohol (16.4 mL), water (7.0 mL), and triethylamine (1.39 mL)were added to crude7-[(7S)-7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-8-methoxy-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid-BF₂ complex (4.67 g). The mixture was stirred for 3 hours underheating at 80° C. Thereafter, the mixture was cooled to roomtemperature, and the precipitated crystals were collected throughfiltration, followed by drying, to thereby yield a crude product of thetitle compound (4.14 g, yield: 98.7%). The crude product (0.20 g) wasrecrystallized from acetonitrile (2.2 mL), to thereby yield the titleproduct as pale yellow crystals (0.135 g, yield: 67.5%).

¹H-NMR (400 MHz, DMSO-D₆) δ ppm: 0.39-0.60 (m, 3H), 0.76-0.81 (m, 1H),1.09 (s, 3H), 1.52-1.65 (m, 2H), 3.49-3.81 (m, 4H), 3.59 (s, 3H),4.05-4.12 (m, 1H), 4.85-5.07 (m, 1H), 7.66 (d, J=14.0, 1H), 8.67 (d,J=1.6 Hz, 1H).

Separately, the crude product was suspended in isopropyl alcohol (about20-fold volume with respect to weight of the crude product), andconcentrated hydrochloric acid (about 1.5-fold volume with respect toweight of the crude product) was added to the suspension, followed bystirring and filtering, to thereby yield a hydrochloric acid salt of thetitle compound.

Theoretically, the compound produced in Example 23 may include twoisomers in terms of the coordination mode of the amino group and themethyl group attached to the carbon atom to which the amino group of thespiropyrrolidinyl group which serves as a 7-position substituent isbound. The quinolone compound produced in Example 23 was found to be anisomer thereof exhibiting higher antibacterial effect. Therefore, thestereoconfiguration of the amine compound produced through racemicresolution in Example 12 was found to be the coordination mode of theamino group and the methyl group for attaining more potent antibacterialeffect.

Example 247-[(7R)-7-Amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-8-methoxy-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Isopropyl alcohol (2.1 mL), water (0.9 mL), and triethylamine (0.18 mL)were added to crude7-[(7R)-7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-8-methoxy-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid-BF₂ complex (0.60 g). The mixture was stirred for 3 hours underheating at 80° C. Thereafter, the mixture was cooled to roomtemperature. The precipitated crystals were collected through filtrationand dried, to thereby yield a crude product of the title compound (0.51g, yield: 95.1%). This crude product (0.30 g) was recrystallized fromacetonitrile (3.0 mL), to thereby yield the title product as pale yellowcrystals (0.20 g, yield: 66.7%).

¹H-NMR (400 MHz, DMSO-D₆) δ ppm: 0.39-0.60 (m, 3H), 0.70-0.80 (m, 1H),1.09 (s, 3H), 1.47-1.59 (m, 2H), 3.51-3.79 (m, 4H), 3.57 (s, 3H),4.03-4.11 (m, 1H), 4.93-5.15 (m, 1H), 7.66 (d, J=14.4, 1H), 8.63 (d,J=2.4 Hz, 1H).

Referential Example 1 t-Butyl5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate

Under stirring by means of an impeller, O-t-butyl-N,N′-diisopropylurea(3,020 g, 15.00 mol) was added at room temperature to a suspension of5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (1,165 g,4.994 mol), which had been produced through the method described in theliterature (i.e., Culbertson T. P., Domagala J. M., Nichols J. F.,Priebe S., and Skeean R. W., J. Med. Chem., 1987, 30, 1711-1715.), indichloromethane (10 L). After an increase in internal temperature andinitiation of reflux had been confirmed, the mixture was cooled in anice-water bath. The reaction mixture was cooled to room temperature.Thereafter, the ice-water bath was removed, and the reaction mixture wasstirred for 1 hour. Subsequently, the mixture was stirred for 3 hoursunder heating at 40° C. The reaction mixture was stirred for 1 hour withcooling in an ice-water bath, and insoluble material was removed throughfiltration. The filtrate was evaporated to dryness under reducedpressure, and the residue was purified through silica gel columnchromatography (silica gel: 4 kg, eluent: hexane:ethyl acetate=3:1), tothereby yield the title compound as pale yellow syrup (3-position isomermixtures) (925.2 g, 64%). The diastereomers in terms of the 3-positionof pyrrolidine can be readily fractionated. However, since thesubsequent step include reaction involving epimerization, thediastereomers were used without performing fractionation. ¹H-NMRspectral data of each diastereomer, which had been separatelyfractionated, are given below.

Low-Polar Isomer:

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.45 (9H, s), 1.54 (3H, d, J=7.08 Hz),2.59-2.74 (2H, m), 2.95-3.03 (1H, m), 3.14 (1H, dd, J=9.77, 8.79 Hz),3.49 (1H, dd, J=9.77, 6.35 Hz), 7.26-7.36 (5H, m).

High-Polar Isomer:

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.36 (9H, s), 1.53 (3H, d, J=7.32 Hz),2.59-2.75 (2H, m), 3.02-3.11 (1H, m), 3.16 (1H, dd, J=10.01, 5.62 Hz),3.51 (1H, dd, J=10.01, 8.54 Hz), 7.24-7.36 (5H, m).

Referential Example 2 t-Butyl(3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid

Under a nitrogen gas atmosphere, iodomethane (26.0 mL, 59.28 g, 0.418mol) and sodium hydride (oil content: 55%, 11.35 g, 0.260 mol) weresequentially added at room temperature to a solution of t-butyl5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (30.05 g,0.104 mol) in N,N′-dimethylformamide (210 mL) with stirring. When theinternal temperature reached to about 50° C., the mixture was cooled to30° C. in an ice-water bath. Subsequently, the bath was changed to awater bath having an external temperature of 17° C., followed bystirring for 23 hours. The reaction mixture was poured into cold aqueouscitric acid (a mixture of 10% citric acid (1 L) and ice (500 g)),followed by stirring for 30 minutes and extracting with ethyl acetate(800 mL, 500 mL). The organic layers were combined. The combined organiclayer was washed with saturated brine, followed by drying over sodiumsulfate anhydrate and filtration. The filtrate was evaporated to drynessunder reduced pressure. The residue was purified through flash silicagel column chromatography (eluent; hexane:ethyl acetate=5:1 to 4:1), tothereby yield the title compound as white solid (10.63 g, 33.7%) as ahigh-polar isomer. In addition, t-butyl(3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid(14.91 g, 47.3%) was produced as a low-polar isomer.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.34 (12H, s), 1.52 (3H, d, J=7.10 Hz),2.27 (1H, d, J=17.0 Hz), 2.93 (1H, d, J=17.0 Hz), 3.05 (1H, d, J=10.1Hz), 3.32 (1H, d, J=10.1 Hz), 5.50 (1H, q, J=7.1 Hz), 7.23-7.38 (5H, m).

Referential Example 3 t-Butyl(3S)-4-[2-(t-butyldimethylsilyl)hydroxyethyl]-3-methyl-5-oxo-1-[(1R)-phenylethyl]pyrrolidine-3-carboxylate

t-Butyl(3S)-3-methyl-5-oxo-1-[(1R)-phenylethyl]pyrrolidine-3-carboxylate (30.0g, 98.9 mmol) and t-butyl (2-iodoethoxy)dimethylsilane (36.8 g, 129mmol) were dissolved in anhydrous tetrahydrofuran (288 mL), and lithiumbis(trimethylsilyl)amide (1.0M tetrahydrofuran solution, 129 mL, 129mmol) was added dropwise to the solution at −4° C., followed by stirringat 2° C. for 3.5 hours. Subsequently, saturated aqueous ammoniumchloride solution (300 mL) was added to the reaction mixture, followedby extraction with ethyl acetate (300 mL, 200 mL). The thus-obtainedorganic layer was washed with saturated brine (200 mL), followed bydrying over sodium sulfate anhydrate and filtration. The filtrate wasevaporated to dryness under reduced pressure, to thereby yield the titlecompound (54.1 g). The thus-obtained compound was used in the next stepwithout any purification.

MS (ESI) m/z: 363 (M-Boc+H)+.

Referential Example 4 t-Butyl(3S)-4-(2-hydroxyethyl)-3-methyl-5-oxo-1-[(1R)-phenylethyl]pyrrolidine-3-carboxylate

The aforementioned crude silyl compound (54.1 g, 98.9 mmol) wasdissolved in tetrahydrofuran (450 mL). A 1.0-mol/L solution oftetrabutylammonium fluoride (148 mmol) in tetrahydrofuran solution mL)was added dropwise to the solution under ice-cooling, and the mixturewas stirred at room temperature for 2 hours. The reaction mixture wasconcentrated, followed by extraction with ethyl acetate (200 mL, 100mL). The thus-obtained organic layer was washed sequentially with 10%aqueous sodium hydrogencarbonate (200 mL), aqueous citric acid (300 mL),and saturated brine (100 mL), followed by drying over sodium sulfateanhydrate and filtration. The filtrate was evaporated to dryness underreduced pressure. The residue was purified through silica gel columnchromatography (eluent; hexane:ethyl acetate=6:1 to 4:1 to 1:1), tothereby yield the title compound as colorless transparent syrup (29.1 g,83.9 mmol, 85%).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.28 (3H, s) 1.40 (9H, s), 1.51-1.53 (1H,m), 1.53 (3H, d, J=7.1 Hz), 1.78-1.94 (2H, m), 2.90-3.08 (2H, m),3.67-3.75 (1H, m), 3.80-3.91 (1H, m), 4.85-4.89 (1H, m), 5.43-5.53 (1H,m), 7.27-7.37 (5H, m).

MS (ESI) m/z: 348 (M+H)+.

Referential Example 5 t-Butyl(3S)-4-[2-(benzenesulfonyl)oxyethyl]-3-methyl-5-oxo-1-[(1R)-phenylethyl]pyrrolidine-3-carboxylate

Triethylamine (15.2 mL, 109 mmol), benzenesulfonyl chloride (11.8 mL,92.3 mmol), and 4-dimethylaminopyrridine (1.02 g, 8.39 mmol) were addedto a solution of t-butyl(3S)-4-(2-hydroxyethyl)-3-methyl-5-oxo-1-[(1R)-phenylethyl]pyrrolidine-3-carboxylate(29.1 g, 83.9 mmol) in dichloromethane (280 mL) under ice-cooling, andthe mixture was stirred at room temperature for 19 hours. Subsequently,saturated aqueous ammonium chloride (280 mL) was added to the reactionmixture. The organic layer was separated, and the solvent thereof wasevaporated under reduced pressure. The residue was dissolved in ethylacetate (280 mL, 180 mL), and the solution was washed again with thesame saturated aqueous ammonium chloride as employed above. The formedorganic layer was washed sequentially with 1-mol/L aqueous hydrochloricacid (250 mL), saturated aqueous sodium bicarbonate (250 mL), andsaturated brine mL), followed by drying over sodium sulfate anhydrateand filtration. The filtrate was evaporated to dryness under reducedpressure, to thereby yield a crude product of the title benzenesulfonylcompound (43.7 g). The thus-obtained compound was used in the subsequentstep without performing purification.

MS (ESI) m/z: 510 (M+Na)+.

Referential Example 6 t-Butyl(7S)-7-methyl-4-oxo-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane-7-carboxylate

A 1.0-mol/L solution of sodium bis(trimethylsilyl)amide intetrahydrofuran (109 mL, 109 mmol) was added under ice-cooling to asolution of the crude benzenesulfonyl compound (43.7 g, 83.9 mmol),which had been produced in the previous step, in anhydroustetrahydrofuran (470 mL). The mixture was stirred at room temperaturefor 1 hour. Subsequently, saturated aqueous ammonium chloride (300 mL)was added to the reaction mixture, followed by extraction with ethylacetate (300 mL, 200 mL). The organic layer was washed with saturatedbrine (200 mL). The formed organic layer was dried over sodium sulfateanhydrate, followed by filtration. The filtrate was evaporated todryness under reduced pressure. The residue was purified through silicagel column chromatography (eluent; hexane:ethyl acetate=3:1 to 2:1), tothereby yield the title compound as white solid (24.6 g, 89%, 2 steps).

mp: 55-57° C.

[α]_(D)25.1=122.1° (c=0.517, CHCl₃).

¹H-NMR (400 MHz, CDCl₃) δ: 0.72-0.77 (1H, m), 0.85-0.90 (1H, m),1.04-1.13 (2H, m), 1.18 (3H, s), 1.32 (9H, s), 1.54 (3H, d, J=7.1 Hz),3.08 (1H, d, J=9.8 Hz), 3.53 (1H, d, J=9.8 Hz), 5.52 (1H, q, J=7.1 Hz),7.26-7.34 (5H, m).

Elemental Analysis; as C₂₀H₂₇NO₃:

Calculated: C, 72.92; H, 8.26; N, 4.25.

Found: C, 72.64; H, 8.27; N, 4.06.

MS (FAB) m/z: 330 (M+H)+.

HRMS (FAB) m/z: 330.2069 (Calcd for C20H28NO3 330.2069).

IR (ATR) ν: 3066, 2976, 2933, 2879, 1720, 1676, 1481, 1454, 1433, 1365,1329, 1286, 1238, 1203 cm⁻¹.

Configuration of the 7-position of the compound was determined throughX-ray structural analysis. FIG. 1 shows the detail structure.

After collection of the data, initial phase was determined through thedirect method and refined by the complete matrix least square method. Inthe refining, an anisotropic thermal factor was applied to non-hydrogenatoms, and the positions of hydrogen atoms were fixed in the coordinatesthrough calculation. The compound of Referential Example 6 contains twoasymmetric carbon atoms, and absolute configuration of one asymmetriccarbon atom is already known. According to this absolute configuration,absolute configuration of the other asymmetric carbon atom wasdetermined.

FIG. 1 shows the results. As shown in FIG. 1, the configuration of the7-position of the title compound was determined as (S). Thus,configuration of a series of compounds prepared from the compound couldalso be determined.

Referential Example 7(7S)-7-Methyl-4-oxo-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane-7-carboxylicacid

Trifluoroacetic acid (120 mL) was added dropwise to a solution oft-butyl(7S)-7-methyl-4-oxo-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane-7-carboxylate(24.5 g, 74.4 mmol) in dichloromethane (120 mL) under ice-cooling,followed by stirring for 2 hours. The reaction mixture was evaporated todryness under reduced pressure. Toluene (20 mL) was added to theresidue, and the mixture was evaporated to dryness under reducedpressure. The residue was dissolved in 1-mol/L aqueous sodium hydroxide(300 mL) under ice-cooling. The resultant aqueous solution was washedwith ethyl acetate (350 mL). Concentrated hydrochloric acid (25 mL) wasadded under ice-cooling to the formed aqueous layer so as to adjust thepH of the layer to 2 to 3, followed by extraction with chloroform (300mL×2). The formed organic layer was washed sequentially with water (200mL) and saturated brine (100 mL). The washed layer was dried over sodiumsulfate anhydrate, and the solvent was evaporated under reducedpressure. Toluene (20 mL) was added to the residue, and the mixture wasevaporated to dryness under reduced pressure. The residue was suspendedin chloroform (20 mL), and hexane (200 mL) was added to the suspensionfor crystallization. The precipitated solid was washed with hexane (100mL) and dried under reduced pressure, to thereby yield the titlecompound as white solid (20.48 g (quantitative)). The thus-obtainedcompound was used in the subsequent step without performingpurification.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.78-0.83 (1H, m) 0.90-0.95 (1H, m),1.08-1.18 (2H, m), 1.24 (3H, s), 1.55 (3H, d, J=7.3 Hz), 3.11 (1H, d,J=10.0 Hz), 3.55 (1H, d, J=10.0 Hz), 5.52 (1H, q, J=7.1 Hz), 7.28-7.32(5H, m).

MS (ESI) m/z: 274 (M+H)+.

Referential Example 8(7S)-7-Amino-7-methyl-4-oxo-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane

(7S)-7-Methyl-4-oxo-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane-7-carboxylicacid (20.4 g, 74.4 mmol) and diphenylphosphoryl azide (17.6 mL, 81.8mmol) were dissolved in toluene (200 mL), and triethylamine (20.7 mL,149 mmol) was added to the solution, followed by stirring under heatingin an oil bath (at 125° C.) for 1 hour. The reaction mixture wasconcentrated under reduced pressure, to thereby yield a crude isocyanatecompound.

The crude isocyanate compound was dissolved in 1,4-dioxane (180 mL), andwater (90 mL) and concentrated hydrochloric acid (90 mL) were added tothe solution, followed by stirring under heating in an oil bath (at 50°C.) for 1 hour. Subsequently, water (200 mL) was added to the reactionmixture, and the mixture was washed with ethyl acetate (200 mL).10-mol/L Aqueous sodium hydroxide (170 mL) was added under ice-coolingto the formed aqueous layer so as to adjust the pH of the layer to 9 to10, followed by extraction with toluene (200 mL×2). The organic layerwas washed with saturated brine (100 mL), dried over sodium sulfateanhydrate, and filtered. The filtrate was concentrated under reducedpressure, to thereby yield the title compound as pale yellow oil (15.8g, 64.7 mmol). The thus-obtained compound was used in the next stepwithout any purification.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.72-0.78 (2H, m), 0.99-1.10 (2H, m),1.08 (3H, s), 1.53 (3H, d, J=7.4 Hz), 2.82 (1H, d, J=9.6 Hz), 3.27 (1H,d, J=9.6 Hz), 5.56 (1H, q, J=7.1 Hz), 7.14-7.37 (5H, m).

Referential Example 9(7S)-7-(t-Butoxycarbonylamino)-7-methyl-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane

The aforementioned(7S)-7-amino-7-methyl-4-oxo-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane(15.8 g, 64.7 mmol) was dissolved in toluene (82 mL). Separately, 65 wt.% sodium bis(2-methoxyethoxy)aluminum hydride (259 mmol) in toluene(77.6 mL) was prepared, and an aliquot (6 mL) of the solution was addeddropwise to the azaspiroheptane solution over 15 minutes. Throughice-cooling, the internal temperature of the reaction mixture wascontrolled so as not to exceed 70° C. The resultant mixture was stirredunder heating in an oil bath (at 80° C.) for 10 minutes. The reactionmixture was ice-cooled, and 25 wt. % aqueous sodium hydroxide (158 mL)was added dropwise thereto for termination of reaction, followed byextraction with toluene (135 mL). The formed organic layer was washedwith saturated brine (100 mL), and di-t-butyl dicarbonate (15.6 g, 71.2mmol) was added to the washed layer. The reaction mixture was stirred atroom temperature for 3 hours, and the solvent was evaporated underreduced pressure. The residue was purified through silica gel columnchromatography (eluent; hexane:ethyl acetate=8:1 to 4:1 to 1:1), tothereby yield the title compound as colorless transparent syrup (18.0 g,73%).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.37-0.49 (2H, m), 0.62-0.68 (1H, m),0.77-0.82 (1H, m), 1.20 (3H, s), 1.32 (3H, d, J=6.6 Hz), 1.44 (9H, s),2.46 (2H, dd, J=33.2, 9.3 Hz), 2.68 (1H, d, J=8.8 Hz), 3.27 (1H, q,J=6.6 Hz), 3.31-3.34 (1H, m), 4.71 (1H, s), 7.19-7.34 (5H, m).

MS (ESI) m/z: 331 (M+H)+.

Referential Example 10(7S)-7-(t-Butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptane

To a solution of(7S)-7-(t-butoxycarbonylamino)-7-methyl-5-[(1R)-phenylethyl]-5-azaspiro[2.4]heptane(18.0 g, 54.5 mmol) in methanol (180 mL), 10% palladium carbon (watercontent: 52.8%, 9.00 g) serving as a catalyst was added, and the mixturewas stirred at room temperature under a hydrogen gas atmosphere for 18hours. The mixture was further stirred in an oil bath (at 40° C.) for5.5 hours. The catalyst was removed through filtration, and the solventwas evaporated to dryness under reduced pressure, to thereby yield acrude product of the title compound as white solid (13.4 g(quantitative)).

¹H-NMR (400 MHz, CDCl₃) δ ppm: 0.38-0.43 (1H, m) 0.54-0.61 (2H, m),0.74-0.80 (1H, m), 1.08 (3H, s), 1.44 (9H, s), 2.75 (1H, d, J=7.6 Hz),2.78 (1H, d, J=7.1 Hz), 3.13 (1H, d, J=11.5 Hz), 3.73-3.77 (1H, m), 4.45(1H, s).

MS (ESI) m/z: 227 (M+H)+.

Referential Example 117-[(7S)-7-Amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

(7S)-7-(t-Butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptane (13.4 g,54.5 mmol),6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid-difluoroboron complex (17.9 g, 49.5 mmol), and triethylamine (8.97mL, 64.4 mmol) were dissolved in dimethyl sulfoxide (52 mL), followed bystirring under heating in an oil bath (at 40° C.) for 17 hours. Thereaction mixture was poured into cold water (1,000 mL), and theprecipitated solid was collected through filtration. Triethylamine (15mL) and a mixture (180 mL) of ethanol and water (5:1) were added to thesolid, followed by refluxing for 1.5 hours. The reaction mixture wasevaporated to dryness under reduced pressure. The residue was dissolvedin ethyl acetate (150 mL×2), followed by washing sequentially with 10%aqueous citric acid (200 mL), water (200 mL), and saturated brine (100mL). The organic layer was dried over sodium sulfate anhydrate, and thesolvent was evaporated under reduced pressure. The residue was dissolvedin a mixture (100 mL) of chloroform and methanol (9:1), and silica gel(10 g) was added to the solution, followed by stirring for 1 hour.Thereafter, silica gel was removed from the mixture through filtration,and the silica gel was washed with a mixture of chloroform and methanol(9:1) (50 mL×2). The filtrate and washings were combined, followed byconcentration to dryness. The residue was dissolved in concentratedhydrochloric acid (200 mL) under ice-cooling, and the solution wasstirred at room temperature for 30 minutes. The reaction mixture waswashed with chloroform (400 mL×5). 10-mol/L Aqueous sodium hydroxide wasadded under ice-cooling to the formed aqueous layer so as to adjust thepH of the layer to 11.8. Subsequently, the pH of the layer was adjustedto 7.4 with hydrochloric acid, followed by extraction with chloroform(1,000 mL×3). The organic layer was dried over sodium sulfate anhydrate,and the solvent was evaporated under reduced pressure. The residue wasrecrystallized from ethanol for purification and dried under reducedpressure, to thereby yield the title compound as pale pink powder (18.5g, 79%).

Analytical data of the resultant product obtained by means ofapparatuses including ¹H-NMR completely coincided with those of thecompound of Example 23. Thus, among quinolone derivatives having a7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl group, the 7-positionconfiguration of the 5-azaspiro[2.4]heptan-5-yl group of the quinolonederivative described in Example 23, which is a highly active compound,was determined as (7S).

The compounds produced in Examples 12, 13, 14, 16, 17, and 20, and thecompound which had been reacted with the boron-chelate compound inExample 21 were (S)-forms. The compounds produced in Examples 15 and 18and the compound which had been reacted with the boron-chelate compoundin Example 22 were (R)-forms.

1. A compound represented by formula (1)

wherein n is an integer of 2 to 5; R¹ represents a C1 to C4 alkyl groupwhich may have a substituent or an aryl group which may have asubstituent; R² represents an alkoxycarbonyl group which may have asubstituent, an aralkyloxycarbonyl group which may have a substituent,an aliphatic acyl group which may have a substituent, or an aromaticacyl group which may have a substituent; and R³ represents a C1 to C4alkyl group which may have a substituent, an aralkyl group which mayhave a substituent, or a hydrogen atom.
 2. The compound as described inclaim 1, wherein, in formula (1), n is
 2. 3. The compound as describedin claim 1, wherein, in formula (1), R² is a t-butyloxycarbonyl group, abenzyloxycarbonyl group, a benzoyl group, or an acetyl group.
 4. Thecompound as described in any one of claim 1, wherein, in formula (1), R¹is a methyl group, an ethyl group, a propyl group, an isopropyl group,or a phenyl group.
 5. The compound as described in any one of claim 1,wherein, in formula (1), R³ is a methyl group or an ethyl group.